AR043057A1 - COMPOUNDS DERIVED FROM PYRIDINTIAZOLES AS INHIBITORS OF QUINASA ROCK AND OTHER PROTEINS QUINASA - Google Patents

COMPOUNDS DERIVED FROM PYRIDINTIAZOLES AS INHIBITORS OF QUINASA ROCK AND OTHER PROTEINS QUINASA

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AR043057A1
AR043057A1 ARP030103973A ARP030103973A AR043057A1 AR 043057 A1 AR043057 A1 AR 043057A1 AR P030103973 A ARP030103973 A AR P030103973A AR P030103973 A ARP030103973 A AR P030103973A AR 043057 A1 AR043057 A1 AR 043057A1
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Argentina
Prior art keywords
phenyl
hydrogen
och3
unsubstituted
optionally substituted
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ARP030103973A
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Spanish (es)
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Jingrong Cao
Huai Gao
Jeremy Green
Craig Marhefka
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Vertex Pharma
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Publication of AR043057A1 publication Critical patent/AR043057A1/en

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Abstract

La presente se refiere a compuestos útiles como inhibidores de las proteínas quinasa, además, provee composiciones farmacéuticamente aceptables que comprenden dichos a compuestos, y métodos para la utilización de las composiciones para el tratamiento de varias enfermedades, condiciones o trastornos proliferativos, inflamatorios, autoinminológicos, neurodegenerativos y usos de los mismos como quimioterapéuticos. Reivindicación 1: Un compuesto de la fórmula (1), o una sal farmacéuticamente aceptable del mismo, caracterizado porque B es una de las estructuras (2), (3), (4), R1 es halógeno, CN, NO2, o VmR; Z1 y Z3 son cada uno independientemente N o CRZ, y Z2 es N o CR1, con la condición de que provided that Z1, Z2 y Z3 no sean simultaneamente N; cada vez que RZ está presente, es independientemente halógeno, CN, NO2, o UnR'; R2 es UnR'; X1 y X2 son cada uno independientemente CR4 o N; cada vez que R4 está presente, es independientemente halógeno, CN, NO2, o VmR; cada vez que está presente, U o V es independientemente una cadena alquilideno C1-6 opcionalmente substituida, donde hasta dos unidades de metileno de la cadena están opcional e independientemente reemplazadas por -NR-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2NR-, -PO-, -PO2- o -POR-; m y n son cada uno independientemente 0 o 1; cada vez que está presente, R es independientemente hidrógeno o un grupo alifático C1-6 opcionalmente substituido; y cada vez que está presente R' es independientemente hidrógeno o un grupo alifático C1-6 opcionalmente substituido, un anillo arilo C1-6 opcionalmente substituido, un anillo heteroarilo opcionalmente substituido que tiene de 5-10 átomos en el anillo, o un anillo heterociclilo opcionalmente substituido, que tiene de 3-10 átomos en el anillo; o R y R', dos R presentes; o dos R' presentes se toman junto con el/los átomo/s a los cuales están unidos para formar un anillo opcionalmente substituido de 3-8 miembros saturado, parcialmente insaturado, o completamente insaturado que tiene 0-4 heteroátomos seleccionados de manera independiente entre nitrógeno, oxígeno, o azufre; Q1 es -CO-, -SO2-, -CONR-, o -SO2NR-; R3 es Q2-Ar, o R2 y Q1-R3, tomados junto con el átomo de nitrógeno, forman el grupo cíclico (5): donde s es 1 o 2, cada vez que está presente Y es independientemente, según la valencia y estabilidad lo permitan, -CO-, -CS-, -SO2-, -O-, -S-, -NR5 -, o -C(R5)2-, y R5 es UnR'; Q2 y Q3 son cada uno independientemente un enlace o una cadena alquilideno C1-6, donde hasta dos unidades de metileno de la cadena son opcional e independientemente reemplazadas por -NR'-, -S-, -O-, -CS-, -CO2-, -OCO-, -CO-, -COCO-, -CONR'-, -NR'CO-, -NR'CO2-, -SO2NR'-, -NR'SO2-, -CONR'NR'-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'SO2NR'-, -SO-, -SO2-, -PO-, -PO2-, o -POR'-; y donde cada átomo de carbono en una o más unidades metileno está opcionalmente substituido con una o R6 presentes, donde cada vez que está presente R6 es independientemente halógeno, CN, NO2, o UnR', o dos R6 presentes, o R' y R6, tomados junto con los átomos a los cuales están unidos, forman un anillo opcionalmente substituido de 3 6 miembros, cicloalquilo, heterociclilo, arilo o heteroarilo; y Ar1 y Ar2 son independientemente un anillo monocíclico que tiene de 5-6 miembros saturado, parcialmente insaturado, o completamente insaturado que tiene de 0-3 heteroátomos seleccionados de manera independiente entre nitrógeno, oxígeno, o azufre, o un sistema de anillo bicíclico que tiene de 8-10 miembros saturado, parcialmente insaturado, o completamente insaturado que tiene de 0-5 heteroátomos seleccionados de manera independiente entre nitrógeno, oxígeno, o azufre; donde Ar1 y Ar2 están cada uno opcionalmente substituido con 0-5 TR7 presentes independientes; donde T es un enlace o es una cadena C1-C6 alquilideno donde hasta dos unidades metileno de T están opcionalmente reemplazadas por -NR-, -S-, -O-, -CS-, -CO2-, -OCO-,-CO-, -COCO-, -CONR-, -NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, o -POR-; y cada vez que aparece R7 es independientemente R', halógeno, NO2, o CN; con la condición de que: I) Para los compuestos descriptos donde B es de la estructura (2) se aplican una o más de, o todas las siguientes condiciones: A) para los compuestos que tienen la estructura (6): i) cuando R1 es Cl, y R2 es -CH(CH3)COOCH3 o hidrógeno, entonces Q1-R3 no es -CO(fenilo no substituido), -CO(2-furilo no substituido), o -COCH2(fenilo no substituido); ii) cuando R1 es hidrógeno, R2 es hidrógeno, y Q1 es -CO-, entonces R3 no es: a) fenilo substituido con 4-O(CH2)4-7CH3 o 4-(CH2)4-7CH3; b) fenilo substituido con 2-Cl, 4-NO2, 4-Cl, 2-Br, 3-Br, 3-I, 3-CH3, 4-OCH3, 3-NO2, o 4-I; c) 2,6-OCH3-fenilo d) (5-Cl, 3-CH3, 1-fenil)-pirazol-4-ilo; o e) 4-OnBu-fenilo, -CH2O(2-F-fenilo), -(CH2)2fenilo, furan-2-ilo, tiofen-2-ilo, 4-CH3-fenilo, -CH2O(2-CH3-fenilo), 3-OCH3-fenilo, 2-(2,5-dimetoxilfenil)quinolin-4-ilo, -NH-(4-Cl-fenilo), -NH-(3,4-diclorofenilo), (2-CO2H, 3-NO2)-fenilo, 3,5-dimetil-isoxazol-4-ilo, -CH=CH-fenilo, 4-F-fenilo, C(CH3)2O-(4-Cl-fenilo), -NH(3-Cl-fenilo), -NHfenilo, fenilo no substituido, 3,4,5-OCH3-fenilo, 4-NO2-fenilo, 4-ciclopentoxi-fenilo, -(CH2)3fenilo, -(triciclo[3.3.1.13,7]decan-1-ilo, -CH2O-(3-CH3-fenilo), 3-NO2-fenilo, -ciclopropil-(4-tert-butil-fenilo), 2,3-OCH3-fenilo, 1,3-benzodioxo-5-ilo, -CH2-O-(4-F-fenilo), o 3-Br-fenilo; iii) cuando R1 es hidrógeno, R2 es hidrógeno, y Q1 es -CSNH-, entonces R3 no es 2,3,4,6-tetra-O-acetil-beta-D-glucopiranosilo; iv) cuando R1 es hidrógeno, R2 es hidrógeno, y Q1 es SO2, entonces R3 no es fenilo no substituido, bencilo no substituido, naftilo no substituido, fenilo substituido con para-NHCOCH3, para-NH2, o para-CH3; y v) cuando R1 es hidrógeno, R2 es -CH2CH-CH2, y Q1 es CO, entonces R3 no es 4-OCH3-fenilo, naftilo no substituido, -NH-(4-OCH3-fenilo), 3,5-OCH3-fenilo, CH2Ofenilo, -CH2-tiofen-2-ilo, o -CH(fenilo)(CH2CH3); y vi) cuando R1 es hidrógeno, R2 es CH2CH3, y Q1 es CO, entonces R3 no es 2,4-Cl-fenilo; y B) para los compuestos que tienen la estructura (7): cuando R2 es hidrógeno o CH3, y Q1 es -CO-, entonces R3 no es -OCH2CH2OCH2fenilo; II) Para los compuestos descriptos, donde B es de fórmula (3) se aplican una o más de, o todas las siguientes condiciones: A) para los compuestos que tienen la estructura (8); i) cuando R3 es Q2-Ar1, y Q2 es un enlace entonces Ar1 no es uno ni más de uno de los siguientes: fenilo no substituido o fenilo substituido con 2-Br; 2-Cl; 2-I; 2,6-F; 3,5-OCH3; 3,4,5-OCH3; 2,4-OCH3; 3,4-CH3; 2,5-Cl; 3,4,-OCH3; 2-Cl, 5-NO2; 3,5-Cl; 3-O(CH2)4CH3, 3-O-n-butilo, 3-CF3, 3-OCH3, 3-Br; 3-NO2; 3-CH3; 3-O-fenilo; 3-Cl; 4-N(CH3)2; 4-N(CH2CH3)2; 4-SO2N(R')2; 4-CN; 4-COOCH3; 4-C(O)fenilo; 4-fenilo; 4-tert-butilo, 4-O-fenilo; 4-O-isopropilo; 4-OCH3; 4-OCH2CH3; 4-O-n-butilo; 4-Cl; 4-Br; 4-F; 4-CH3; 4-NO2; 4-Cl; 3-NO2, 4-morfolino; 3-NO2, 2,5-dioxopirrolidinilo, o 4-piperidinilo; y ii) R3 no es uno ni más de uno de los siguientes grupos: fórmula (9), fórmula (10), -CH-CH(tiofen-2-ilo), -CH-CH-fenilo no substituido, -CH2(3-NHCOPh-fenilo), -6-bromo-2-(4-etilfenil)-4-quinolinilo, -CH2-pirrolidina, ciclohexilo no substituido, bencilo no substituido, furan-2-ilo no substituido, -CH-CH(3-NO2fenilo), -CH-CH(4-NO2-fenilo), -CH2-naftilo, naftilo no substituido, tiofeno no substituido, ciclopropilo no substituido, 1,4-benzodioxin, 2-oxo-1-benzopirano, 4-oxo-1-benzopirano, 2-tienil-quinolin-4-ilo, 3-cloro-benzo[b]tiofen-2-ilo, 5-Br-(tiofen-2-ilo), 5-Cl-(tiofen-2-ilo), 5-NO2(tiofen-2-ilo), 5-NO2(furan2-ilo), 2,5-Cl-(tiofen-3-ilo), -CH-CH-(5-NO2-tiofen-2-ilo), 5-NO2-(benzotiofen-2-ilo), 3-OCH3-(naft-2-ilo), -CH2O(2,4-Cl-fenilo), -(CH2)2S-fenilo, 2-fenil-quinolin-4-ilo, -CH2O(4-Cl-fenilo), -CH2CH2-3-(4-Cl-fenil)-1-fenil-1-fenil-1-H-pirazol-4ilo, o -CH2(1,3-dioxoisoindol); y B) para los compuestos que tienen la estructura (11): i) cuando R1 es Cl, y X1 es C-Cl, entonces R3 no es NHSO2-(2-CF3-fenilo) o -NHSO2-(2,6-dimetoxi-fenilo); ii) cuando R1 es CH3, y X1 es C-CH3, entonces R3 no es un indol opcionalmente substituido o dihidroindol opcionalmente substituido; y C) para compuestos de la fórmula general (1), cuando Z1, Z2 y Z3 son, cada uno, CH, R1 es H, X1 es CH y X2 es C-COOCH3, entonces R3 no es 2-(4-etil-fenil)-6-bromo-quinolin-4-ilo; y III. Para los compuestos descriptos anteriormente, donde B es de fórmula (4) se aplican una o más de, o todas las siguientes condiciones: A) cuando Z1, Z2 y Z3 son cada uno CH, X2 es N, X1 is CH, Q1 es -CONR-, y R2 es hidrógeno o -CH3, entonces R3 no es piridilo opcionalmente substituido, tiazol-4-ilo opcionalmente substituido, -CH2piridilo, benzimidazol-4-ilo, quinolin-2-ilo, 1-bromo-isoquinolin-3-ilo, benzotiazol-2-ilo, 5,6,7,8-tetrahidro-naftiridin-2-ilo opcionalmente substituido, o fenilo substituido con -CH2piperidinilo; y B) cuando Z1, Z2 y Z3 son cada uno CH, X2 es N, X1 es CH, Q1 es SO2, y R2 es hidrógeno, entonces R3 no es fenilo substituido con la estructura (12) donde R'' es hidrógeno o -COCH3; C) cuando Z1, Z2 y Z3 son cada uno CH, X1 es C-CO2H, X2 es CH, R2 es hidrógeno, y Q1 es SO2, entonces R3 no es 2-CH3-fenilo; y D) cuando Z1, Z2 y Z3 son cada uno CH, X1 es CH, X2 es N, R2 es hidrógeno, y Q1 es CO, entonces R3 no es 5-metoxi-6-trifluorometil-1H-indol.This refers to compounds useful as protein kinase inhibitors, in addition, it provides pharmaceutically acceptable compositions comprising said compounds, and methods for the use of the compositions for the treatment of various proliferative, inflammatory, autoinminological diseases, conditions or disorders, neurodegenerative and uses thereof as chemotherapeutics. Claim 1: A compound of the formula (1), or a pharmaceutically acceptable salt thereof, characterized in that B is one of the structures (2), (3), (4), R1 is halogen, CN, NO2, or VmR ; Z1 and Z3 are each independently N or CRZ, and Z2 is N or CR1, with the proviso that provided that Z1, Z2 and Z3 are not simultaneously N; each time RZ is present, it is independently halogen, CN, NO2, or UnR '; R2 is UnR '; X1 and X2 are each independently CR4 or N; each time R4 is present, it is independently halogen, CN, NO2, or VmR; each time it is present, U or V is independently an optionally substituted C1-6 alkylidene chain, where up to two methylene units of the chain are optionally and independently replaced by -NR-, -S-, -O-, -CS- , -CO2-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO2-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, - OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2NR-, -PO-, -PO2- or -POR-; m and n are each independently 0 or 1; each time it is present, R is independently hydrogen or an optionally substituted C1-6 aliphatic group; and whenever R 'is present is independently hydrogen or an optionally substituted C1-6 aliphatic group, an optionally substituted C1-6 aryl ring, an optionally substituted heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring optionally substituted, which has 3-10 atoms in the ring; or R and R ', two R present; or two R 'present are taken together with the atom (s) which are joined to form an optionally substituted 3-8 saturated, partially unsaturated, or completely unsaturated ring having 0-4 heteroatoms independently selected from nitrogen , oxygen, or sulfur; Q1 is -CO-, -SO2-, -CONR-, or -SO2NR-; R3 is Q2-Ar, or R2 and Q1-R3, taken together with the nitrogen atom, form the cyclic group (5): where s is 1 or 2, each time it is present Y is independently, according to valence and stability allow it, -CO-, -CS-, -SO2-, -O-, -S-, -NR5 -, or -C (R5) 2-, and R5 is UnR '; Q2 and Q3 are each independently a bond or a C1-6 alkylidene chain, where up to two methylene units of the chain are optionally and independently replaced by -NR'-, -S-, -O-, -CS-, - CO2-, -OCO-, -CO-, -COCO-, -CONR'-, -NR'CO-, -NR'CO2-, -SO2NR'-, -NR'SO2-, -CONR'NR'-, -NR'CONR'-, -OCONR'-, -NR'NR'-, -NR'SO2NR'-, -SO-, -SO2-, -PO-, -PO2-, or -POR'-; and where each carbon atom in one or more methylene units is optionally substituted with one or R6 present, where each time R6 is independently halogen, CN, NO2, or UnR ', or two R6 present, or R' and R6 , taken together with the atoms to which they are attached, form an optionally substituted 3-membered ring, cycloalkyl, heterocyclyl, aryl or heteroaryl; and Ar1 and Ar2 are independently a monocyclic ring having 5-6 members saturated, partially unsaturated, or completely unsaturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bicyclic ring system that it has 8-10 members saturated, partially unsaturated, or completely unsaturated which has 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where Ar1 and Ar2 are each optionally substituted with 0-5 TR7 independent present; where T is a bond or is a C1-C6 alkylidene chain where up to two methylene units of T are optionally replaced by -NR-, -S-, -O-, -CS-, -CO2-, -OCO -, - CO -, -COCO-, -CONR-, -NRCO-, -NRCO2-, -SO2NR-, -NRSO2-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -NRSO2NR-, -SO-, -SO2-, -PO-, -PO2-, or -POR-; and whenever R7 appears it is independently R ', halogen, NO2, or CN; with the proviso that: I) For the compounds described where B is of the structure (2) one or more of, or all of the following conditions apply: A) for the compounds having the structure (6): i) when R1 is Cl, and R2 is -CH (CH3) COOCH3 or hydrogen, then Q1-R3 is not -CO (unsubstituted phenyl), -CO (unsubstituted 2-furyl), or -COCH2 (unsubstituted phenyl); ii) when R1 is hydrogen, R2 is hydrogen, and Q1 is -CO-, then R3 is not: a) phenyl substituted with 4-O (CH2) 4-7CH3 or 4- (CH2) 4-7CH3; b) phenyl substituted with 2-Cl, 4-NO2, 4-Cl, 2-Br, 3-Br, 3-I, 3-CH3, 4-OCH3, 3-NO2, or 4-I; c) 2,6-OCH3-phenyl d) (5-Cl, 3-CH3, 1-phenyl) -pyrazol-4-yl; oe) 4-OnBu-phenyl, -CH2O (2-F-phenyl), - (CH2) 2phenyl, furan-2-yl, thiophene-2-yl, 4-CH3-phenyl, -CH2O (2-CH3-phenyl ), 3-OCH3-phenyl, 2- (2,5-dimethoxyphenyl) quinolin-4-yl, -NH- (4-Cl-phenyl), -NH- (3,4-dichlorophenyl), (2-CO2H, 3-NO2) -phenyl, 3,5-dimethyl-isoxazol-4-yl, -CH = CH-phenyl, 4-F-phenyl, C (CH3) 2O- (4-Cl-phenyl), -NH (3 -Cl-phenyl), -NHphenyl, unsubstituted phenyl, 3,4,5-OCH3-phenyl, 4-NO2-phenyl, 4-cyclopentoxy-phenyl, - (CH2) 3phenyl, - (tricycle [3.3.1.13.7 ] decan-1-yl, -CH2O- (3-CH3-phenyl), 3-NO2-phenyl, -cyclopropyl- (4-tert-butyl-phenyl), 2,3-OCH3-phenyl, 1,3-benzodioxo -5-yl, -CH2-O- (4-F-phenyl), or 3-Br-phenyl; iii) when R1 is hydrogen, R2 is hydrogen, and Q1 is -CSNH-, then R3 is not 2.3 , 4,6-tetra-O-acetyl-beta-D-glucopyranosyl; iv) when R1 is hydrogen, R2 is hydrogen, and Q1 is SO2, then R3 is not unsubstituted phenyl, unsubstituted benzyl, unsubstituted naphthyl, phenyl substituted with para-NHCOCH3, para-NH2, or para-CH3; and v) when R1 is hydrogen, R2 is -CH2CH-CH2, and Q1 is CO, then R3 is not 4-OCH3-phenyl, unsubstituted naphthyl, -NH- (4-OCH3-phenyl), 3,5-OCH3- phenyl, CH2Ophenyl, -CH2-thiophene-2-yl, or -CH (phenyl) (CH2CH3); and vi) when R1 is hydrogen, R2 is CH2CH3, and Q1 is CO, then R3 is not 2,4-Cl-phenyl; and B) for compounds having structure (7): when R2 is hydrogen or CH3, and Q1 is -CO-, then R3 is not -OCH2CH2OCH2phenyl; II) For the compounds described, where B is of formula (3) one or more of, or all of the following conditions apply: A) for the compounds having the structure (8); i) when R3 is Q2-Ar1, and Q2 is a bond then Ar1 is not one or more of one of the following: unsubstituted phenyl or phenyl substituted with 2-Br; 2-Cl; 2-I; 2,6-F; 3,5-OCH3; 3,4,5-OCH3; 2,4-OCH3; 3,4-CH3; 2,5-Cl; 3,4, -OCH3; 2-Cl, 5-NO2; 3,5-Cl; 3-O (CH2) 4CH3, 3-O-n-butyl, 3-CF3, 3-OCH3, 3-Br; 3-NO2; 3-CH3; 3-O-phenyl; 3-Cl; 4-N (CH3) 2; 4-N (CH2CH3) 2; 4-SO2N (R ') 2; 4-CN; 4-COOCH3; 4-C (O) phenyl; 4-phenyl; 4-tert-butyl, 4-O-phenyl; 4-O-isopropyl; 4-OCH3; 4-OCH2CH3; 4-O-n-butyl; 4-Cl; 4-Br; 4-F; 4-CH3; 4-NO2; 4-Cl; 3-NO2, 4-morpholino; 3-NO2, 2,5-dioxopyrrolidinyl, or 4-piperidinyl; and ii) R3 is not one or more of one of the following groups: formula (9), formula (10), -CH-CH (thiophene-2-yl), -CH-CH-unsubstituted phenyl, -CH2 ( 3-NHCOPh-phenyl), -6-bromo-2- (4-ethylphenyl) -4-quinolinyl, -CH2-pyrrolidine, unsubstituted cyclohexyl, unsubstituted benzyl, unsubstituted furan-2-yl, -CH-CH ( 3-NO2phenyl), -CH-CH (4-NO2-phenyl), -CH2-naphthyl, unsubstituted naphthyl, unsubstituted thiophene, unsubstituted cyclopropyl, 1,4-benzodioxin, 2-oxo-1-benzopyran, 4- oxo-1-benzopyran, 2-thienyl-quinolin-4-yl, 3-chloro-benzo [b] thiophene-2-yl, 5-Br- (thiophene-2-yl), 5-Cl- (thiophene-2 -yl), 5-NO2 (thiophene-2-yl), 5-NO2 (furan2-yl), 2,5-Cl- (thiophen-3-yl), -CH-CH- (5-NO2-thiophene- 2-yl), 5-NO2- (benzothiophene-2-yl), 3-OCH3- (naphth-2-yl), -CH2O (2,4-Cl-phenyl), - (CH2) 2S-phenyl, 2 -phenyl-quinolin-4-yl, -CH2O (4-Cl-phenyl), -CH2CH2-3- (4-Cl-phenyl) -1-phenyl-1-phenyl-1-H-pyrazole-4yl, or - CH2 (1,3-dioxoisoindole); and B) for compounds having structure (11): i) when R1 is Cl, and X1 is C-Cl, then R3 is not NHSO2- (2-CF3-phenyl) or -NHSO2- (2,6- dimethoxy-phenyl); ii) when R1 is CH3, and X1 is C-CH3, then R3 is not an optionally substituted indole or optionally substituted dihydroindole; and C) for compounds of the general formula (1), when Z1, Z2 and Z3 are each, CH, R1 is H, X1 is CH and X2 is C-COOCH3, then R3 is not 2- (4-ethyl -phenyl) -6-bromo-quinolin-4-yl; and III. For the compounds described above, where B is of formula (4) one or more of, or all of the following conditions apply: A) when Z1, Z2 and Z3 are each CH, X2 is N, X1 is CH, Q1 is -CONR-, and R2 is hydrogen or -CH3, then R3 is not optionally substituted pyridyl, optionally substituted thiazol-4-yl, -CH2pyridyl, benzimidazol-4-yl, quinolin-2-yl, 1-bromo-isoquinolin-3 -yl, benzothiazol-2-yl, optionally substituted 5,6,7,8-tetrahydro-naphthyridin-2-yl, or phenyl substituted with -CH2piperidinyl; and B) when Z1, Z2 and Z3 are each CH, X2 is N, X1 is CH, Q1 is SO2, and R2 is hydrogen, then R3 is not phenyl substituted with the structure (12) where R '' is hydrogen or -COCH3; C) when Z1, Z2 and Z3 are each CH, X1 is C-CO2H, X2 is CH, R2 is hydrogen, and Q1 is SO2, then R3 is not 2-CH3-phenyl; and D) when Z1, Z2 and Z3 are each CH, X1 is CH, X2 is N, R2 is hydrogen, and Q1 is CO, then R3 is not 5-methoxy-6-trifluoromethyl-1H-indole.

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